An adhesive is a material that is used to bond an object to the surface of another object. According to the International Standards Organization (ISO), “adhesion” is defined as the state in which two surfaces are held together by chemical or physical forces or both, and “adhesive” is a material capable of holding at least two surfaces together. Adhesives are widely used in daily life and various industrial fields due to their convenience and are classified according to their main component into organic adhesives and inorganic adhesives. The organic adhesives are classified into synthetic organic adhesives and natural organic adhesives, and the synthetic organic adhesives are classified into resin-based adhesives including thermosetting resin or thermoplastic resin, rubber-based resins, and mixed adhesives including phenol and epoxy. However, the synthetic organic adhesives have the problem of emitting harmful substances. This problem is caused by the use of volatile organic solvents among organic solvents and volatilization of unreacted monomers. Particularly, in the case of adhesives for use in interior materials for buildings, regulations regarding the emission of harmful substances such as formaldehyde have been strengthened. Under these circumstances, glue-, soy bean protein- and tannin-based adhesives have been developed.
“Pressure sensitive adhesive” may appear as a kind of adhesives and refers to a material that adheres sufficiently to an adherend even by finger pressure, has a low cohesive force and shows a quick stress relaxation compared to an adhesive, and shows a viscoelastic behavior that can be readily deformed by external forces. Raw materials that are used in pressure sensitive adhesives are natural rubber, synthetic rubber, and thermoplastic resins such as acrylic resin and silicone resin, and mostly have elasticity. Unlike adhesives, pressure sensitive adhesives can maintain their adhesive forces even when being repeatedly used several times and have a property that they adhere stickily to adherends, which is called “stickiness”.
Research and development in the field of tissue adhesives, including sealants and hemostats, is growing rapidly. Since a fibrin sealant was approved by the US FDA in the year 1998, new tissue adhesives have been developed annually. Such tissue adhesives are spotlighted as materials capable of substituting for technologies such as suturing, clipping or cautery, which are used in conventional surgical operations or medical procedures.
Conventional surgical techniques such as suturing have strong tensile strength, but suffer from problems such as patient's pain and post-surgical removal. Meanwhile, tissue adhesives have many advantages in that these adhere within a short time, are convenient to use and do not need to be removed after surgery, but have shortcomings in their adhesiveness and tensile strength are low and their adhesiveness significantly decreases in the presence of water. Studies have been conducted to overcome such shortcomings of tissue adhesives.
Tissue adhesives come in direct contact with tissue, and thus are required to be biocompatible. In addition, adhesives for medical use are generally used in vivo, and when they flow into body fluids and blood, they are involved in vivo, and for this reason, they should be free of toxicity and harmfulness under more strict conditions and should be biocompatible and biodegradable.
Generally, tissue adhesives are used in various areas, including skin, blood vessels, digestive system, brain nerve, plastic surgery, orthopedic surgery and the like, and thus they requires different properties, but mainly require the following characteristics: 1) they should adhere quickly at room temperature and atmospheric pressure even in the presence of water; 2) they should be non-toxic and should be able to be sterilized; 3) they should maintain sufficient mechanical strength in close contact with the wound surface; 4) they should be biodegradable and should be able to exhibit a hemostatic effect; and 5) they should be effective in the healing of the body.
Tissue adhesives that are currently commercialized or practically used include cyanoacrylate instant adhesives, fibrin glue, gelatin glue and polyurethane-based adhesives. The cyanoacrylate instant adhesives have recently received attention in studies on instant adhesives having high functionality and high performance. Particularly, medical instant adhesives for tissue suture having biocompatibility, flexibility and low toxicity have hemostatic and antibacterial effects and can substitute for suture materials, and thus have been actively studied mainly in advanced countries.
Such cyanoacrylate-based tissue adhesives are currently commercially available under trade names such as Dermabond (Johnson & Johnson) and Indermil (US Surgical). Such cyanoacrylate-based tissue adhesives have advantages in that they are composed of single materials, are hardened by water within a short time even in the absence of an initiator and have a transparent appearance and high adhesive strength, but have disadvantages of low impact resistance and heat resistance. In addition, these adhesives are not substantially used due to their high toxicity and are partially used in clinical applications in countries other than the USA, but the use thereof is limited due to the tissue toxicity and side effect thereof.
Moreover, the fibrin glue adhesive was approved in 1998 by the US FDA for use in cardiac surgery. Since then, studies on fibrin tissue adhesives have been actively conducted, and products such as Tisseel VH (Baxer) and Evicel™ (Johnson & Johnson) are currently commercially available.
The fibrin tissue adhesives together with the cyanoacrylate-based adhesives account for the tissue adhesive market.
The fibrin tissue adhesives are clinically used to suture peripheral nerves and microvascular blood vessels, based on the cross-linking of fibrin, include fibrinogen, thrombin, calcium chloride and enzyme inhibitors.
Such fibrin glue adhesives have advantages in that they adhere quickly to target tissue without being influenced by water, can form a clot in conjunction with platelets without restrictions and have excellent biocompatibility. However, these have shortcomings in that they have a low adhesive strength, are quickly biodegraded and have the risk of infection.
Moreover, the gelatin glues are tissue adhesives derived from biological tissue and include a cross-linking product of gelatin-resorsinol-formalin (GRF).
In addition, there are tissue adhesives made of gelatin-glutaraldehyde. Although these tissue adhesives provide high adhesiveness, formalin or glutaraldehyde undergo crosslinking reactions with proteins in vivo, giving rise to tissue toxicity.
Developed as flexible adhesives, polyurethane adhesives can maintain the closures in their natural state following solidification. These adhesives absorb water from tissue surfaces to stick themselves fast to the tissues. They react with water to be hardened within several minutes and the hardened adhesives biodegrade properly in addition to being flexible. However, aromatic diisocyanate, a material used in polyurethane adhesives, is toxic to the body.
Thus, the tissue adhesives developed so far still have disadvantages in terms of toxicity and weak adhesiveness. To overcome these problems, studies on 3,4-dihydroxyphenyl-L-alanine (DOPA) that is a sea mussel-derived protein have recently been conducted.
Dopa is a naturally occurring amino acid and derived from the foot protein existed in the foot of mussels. It is the amino acid obtained by hydroxylation of tyrosine by polyphenol oxidase. This amino acid forms a very strong hydrogen bond with hydrophilic surfaces and a strong coordinate covalent bond with metals or semi-metals. Being oxidized to dopa-quinone, dopa residues function to crosslink protein molecules.
Dopa-based tissue adhesives are commercially available, identified as Cell-Tak™ (BD Bioscience Clontech) and MAP™ (Swedish BioScience Lab.). However, these products require as many as 10,000 mussels to make 1 gram of the foot protein. Such a low extraction yield and high production cost restrict the use of the adhesive. In practice, the products are used mainly in cell or tissue culturing.
According to a search on the USPTO database, only 14 patents have been filed with an abstract or claims containing chitosan and adhesive. Most of these patents are for the paper industry. U.S. Pat. No. 5,773,033 disclosed fibrinogen/chitosan hemostatic agents, but not for use in tissue bonding. U.S. Pat. No. 6,329,337 entitled “Adhesive for Biological Tissue” disclosed a glue agent produced from a recombinant human plasma protein and bifunctional or multifunctional aldehydes. Chitosan was used in the agent to enhance the viscosity of the solution or as a crosslinking reagent with bifunctional or multifunctional aldehydes. U.S. Pat. No. 5,496,872 disclosed chitosan in a fairly exhaustive list of potential reagents, but relies on thiols, carboxylic acids and radicals to bond. U.S. Pat. No. 6,200,595 disclosed a combination of polycationic substrates, including chitosan, along with polyanionic substrates to be used as a potential medical adhesive. Reported bond strengths in this patent did not exceed 70 g-f/cm2. Additionally, this invention requires mixing of two components immediately prior to use. U.S. Pat. No. 6,991,652 disclosed the use of chitosan as one in a list of many potential materials to be used as a matrix for cellular growth.
A survey of the literature revealed that dialysis of chitosan has been used as a purification step and as a means for introducing coadditives. For example, U.S. Pat. No. 6,310,188 utilizes dialysis of chitosan to remove low-molecular-weight compounds.
Although a number of systems have been considered for use in the area of tissue adhesives, the currently available systems suffer from deficiencies including toxicity, insufficient strength, or difficulty in use. Thus, there is a need in the art for additional compositions that are safe and effective tissue adhesives that can be provided in a sterile and easy-to-use form. Such highly adherent compositions would also offer significant advantages in drug delivery. There is also a need in the art for compositions that remain highly hydrated, offering novel fillers, bulking compositions, or reconstructive compositions for use in cosmetic and reconstructive surgical procedures.